The ability of human skeletal muscle to perform work over a period of time is critical to the maintenance of health and competent physical functioning. In old age, there are profound changes that occur in the neuromuscular system, many of which are exacerbated by disuse. In this project we will continue pursuit of our long-term goal of elucidating the mechanisms and impact of skeletal muscle fatigue in aging humans by integrating measures of neural, contractile and metabolic function to test novel hypotheses related to the ability of old muscle to produce energy and force. At the same time, we will provide new information about fatigue (defined as the fall of maximal force-generating capacity) in older adults with early signs of impaired physical function. Our Specific Aims are to determine the effects of: 1) old age and physical impairment on the neural and muscular components of muscle metabolic economy, and 2) age and physical impairment on the mechanisms of muscle fatigue. To accomplish our goals, we will use an integrative approach in which we measure the neural signals to the muscle, the ability of the muscle to provide energy, and its capacity to maintain vigorous contractions. This unique set of studies will be conducted using state-of-the-art methodologies, including in-dwelling electrodes and non-invasive magnetic resonance spectroscopy and imaging. Using a cross-sectional design, we will compare the magnitude and mechanisms of muscle fatigue, while accounting for differences in physical activity level and physical functioning in our study subjects. Over the course of this 4-year project, we will study the ankle dorsiflexor muscles of young (aged 21-35 years) and older (65-80) healthy and mobility-impaired men and women. The dorsiflexors provide an excellent model for the planned studies, and they are particularly important to competent locomotion. This project will provide a unique body of knowledge about how neural and metabolic factors may mediate age-related changes in fatigue resistance in a range of older subjects. We will address the long-standing gap that exists in our understanding of how the neural, contractile and metabolic systems are integrated to regulate neuromuscular function in young and older adults, and how that integration may be disrupted with the decline in physical performance in the elderly. PULBIC HEALTH RELEVANCE: The age-related changes in the neuromuscular system are profound. Despite the vital importance of the neuromuscular system to health and independence in old age, the interactions between and regulation of the neural, energetic and muscular factors that support competent physical functioning are not clear at this time. By addressing these key gaps in knowledge, we will respond to two important priorities in geriatric research: 1) we will determine the ability of both healthy and physically-impaired older adults to "respond to the stressor" of muscular work, and 2) we will identify potential "preventable aspects of frailty" relatively early in the impairment-disability-frailty cascade.